Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-methyl-D-aspartate receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of non-rapid eye movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

中文翻译：

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NMDA受体缺乏症人类模型中突触可塑性的改变的EEG标记物：抗NMDA受体脑炎

突触强度和密度的可塑性是实现记忆巩固，学习和神经发育的重要机制。它强烈依赖于N-甲基-D-天冬氨酸受体（NMDAR）的完整功能。NMDAR的功能障碍与许多疾病有关，例如精神分裂症，阿尔茨海默氏病，神经发育障碍和癫痫病，这进一步证明了NMDAR的重要性。突触可塑性被认为是通过整个晚上的睡眠慢波斜率的变化来反映的，即，在睡眠开始时觉醒后比在睡眠后更高的斜率。因此，从理论上讲，功能性NMDAR缺陷应导致改变慢波斜率的过夜变化。在这里，我们调查了小儿患者是否患有抗NMDAR脑炎，由于针对受体亚基的自身抗体而引起的NMDAR缺乏症的一种非常罕见但独特的人类模型，确实显示了这种睡眠EEG标志物对突触可塑性的改变。我们回顾性分析了9名患者（年龄4.3-20.8岁，女性7名）的12个整夜脑电图，并将它们与具有相同年龄分布的45名健康个体的对照组进行了比较。计算患者和对照组（因素“组”）的非快速眼动睡眠（NREM）的第一个小时和最后一个小时（因素“小时”）的慢波斜率。“小时”和“小组”之间存在着重大的互动（7位女性），并将其与45位年龄相同的健康个体的对照组进行比较。计算患者和对照组（因素“组”）的非快速眼动睡眠（NREM）的第一个小时和最后一个小时（因素“小时”）的慢波斜率。“小时”和“小组”之间存在着重大的互动（7位女性），并将其与45位年龄相同的健康个体的对照组进行比较。计算患者和对照组（因素“组”）的非快速眼动睡眠（NREM）的第一个小时和最后一个小时（因素“小时”）的慢波斜率。“小时”和“小组”之间存在着重大的互动（p = 0.013），患者的慢波斜率过夜下降幅度小于对照组。此外，我们发现患者头一小时的斜率较小（p = 0.022），而NREM睡眠的最后一小时则无明显差异（p= 0.980）。重要的是，各组之间的睡眠阶段分布没有区别，在我们对没有严重影响睡眠结构的患者的主要分析中，慢波的发生率也没有。因此，这些可能的混杂因素无法解释慢波斜率值的差异，我们在对整个脑电图样本进行分析时也看到了这一点。这些结果表明，慢波特征的定量EEG分析可能显示抗NMDAR脑炎（一种功能性NMDAR缺乏症的人类模型）患者的突触可塑性受损。因此，将来，睡眠慢波斜率的变化可能会促进功能性NMDAR缺乏和突触可塑性的电生理生物标志物的发展。